Benzodiazepines and related compounds bind to unique receptor sites in the brain and modify the postsynaptic effects of GABA. A large amount of evidence suggests that these ligands can exert profound effects on anxiety and on the formation of memory in humans and laboratory animals. There are several forms of the GABA-A/benzodiazepine receptor based on differential assembly of a series of subunits. Recent studies have suggested that receptors containing the alpha5 subunit are primarily localized in the hippocampus and may be specifically involved in the regulation of synaptic events underlying learning and memory. Our preliminary results indicate that inverse agonists with a high degree of selectivity for alpha5-containing receptor isoforms can enhance certain forms of memory in rats. The present study involves the design and synthesis of a series of novel alpha5-selective ligands that we will evaluate for their ability to modulate hippocampal-dependent and hippocampal-independent forms of memory using a Pavlovian fear conditioning paradigm with mice and rats. A subset of these compounds will be applied directly to the dorsal hippocampus to evaluate possible mechanism of action within this structure. The development of subsite selective agonists and antagonists at GABA-A/BzR receptors will provide important new tools in the investigation of the basic neural mechanisms of memory and anxiety and improve our understanding of benzodiazepine pharmacology. Drugs that enhance memory in the absence of unwanted side effects may prove to be important therapeutic agents in treating disorders of memory due to illness or aging.